THBS1 facilitates colorectal liver metastasis through enhancing epithelial-mesenchymal transition.

ABSTRACT

OBJECTIVE: Liver metastasis is one of the major causes of cancer-related death in patients with colorectal cancer (CRC). The purpose of this study was to identify specific molecules which are involved in colorectal liver metastasis (CRLM). MATERIALS AND METHODS: In this study, we employed TMT (tandem mass tags)-labeling combined with liquid chromatography-mass spectrometry technology to do comparative analyses of proteomics between the primary tumor specimens derived from colorectal cancer patients with or without liver metastasis. Pathway enrichment analyses were performed using DAVID database. The crucial molecules were identified through protein-protein interaction network. Immunohistochemistry (IHC) was employed to analyze the expression of THBS1 (thrombospondin-1) in CRC tissues. Finally, transwell cell migration and invasion assays were performed to explore the roles of THBS1 in CRC cell migration and invasion. RESULTS: We found that the expression of 311 proteins was dysregulated in CRLM using quantitative proteomics. Among these proteins, we identified FN1, TIMP1, THBS1, POSTN and VCAN as five crucial proteins in CRLM by analysis in silico. IHC assay revealed that increased THBS1 expression was significantly correlated with liver metastasis as well as poor prognosis of CRC patients. GEO data analysis also suggests that upregulated mRNA level of THBS1 is also associated with shorter overall survival of CRC patients. Moreover, THBS1 depletion inhibited migration and invasion of CRC cells through attenuating epithelial-mesenchymal transition. Co-expression analyses with TCGA data indicated that THBS1 is co-expressed with mesenchymal markers, including Vimentin, N-cadherin, Snail1 and Twist1 in CRC tissues. CONCLUSIONS: By collecting the omics data with functional studies, the present results reveal that THBS1 facilitates colorectal liver metastasis through promoting epithelial-mesenchymal transition. This understanding of molecular roles of THBS1 in CRLM may be promising to develop targeted therapies to prolong survival in CRC patients.